Ovarian cancer is the fifth leading causes of death from cancer among women throughout the world, and accounts for the death of approximately 16,000 women in the United States each year (Young, “Gynecologic Malignancies,” in J. N. Jameson, D. L. Kasper, T. R. Harrison, E. Braunwald, A. S. Fauci, S. L. Hauser, D. L. Longo (eds.) Harrison's Principles of Internal Medicine, 16th Edition, McGraw-Hill, New York, N.Y., 2005). Although there have been many recent advances for effectively treating this disease (Goff et al., “Ovarian carcinoma diagnosis,” Cancer 89: 2068-2075, 2000; Chobanian and Dietrich, “Ovarian Cancer,” Surg. Clin. North Amer. 88:285-299, 2008), successful intervention still relies heavily on early detection and surgical removal. Therefore, a pressing need exists for the development of new non-surgical methods of treatment that are effective in terms of providing long-term survival for patients, and precise methods for identifying and evaluating changes in tumor burden.
Pancreatic cancer is the eighth most frequent type of solid tumor arising worldwide, but, as a consequence of the current lack of effective therapy, it is the fourth most frequent cause of cancer death (Gunzburg and Salmons, Trends Mol. Med. 7(1):30-37, 2001). It is estimated that 29,200 cases will be diagnosed in the United States in 2001, and 28,900 of these patients are expected to die (Cancer Facts and Figures, 2001. Atlanta, Ga., American Cancer Society, 2001). Long-term survival for patients with organ-confined disease is only 20 percent, and in the majority of cases, in which the disease, when diagnosed, has already spread past the pancreas, survival is only 4 percent (Hilgers and Kern, Genes, Chromosomes & Cancer 26: 1-12, 1999; Regine et al., Front. Biosci. 3: E186-E192, 1998; Blaszkowsky, Front. Biosci. 3:E214-E225, 1998; Lorenz et al., Eur. J. Cancer 36:957-965, 2000; Rosenberg, Drugs 59:1071-1089, 2000).
As the most common internal cancer in older men and the seventh most common cause of death in men of all ages in developed countries, cancer of the prostate is a serious health problem in terms of drawn-out personal suffering and premature death not to mention the cost to the health care system. The incidence of prostate cancer appears to be increasing, over and above improved detection rates in recent years (Post et al., 1999). Although many men with cancer of the prostate die from other causes, the high incidence results in significant morbidity and death directly from the prostatic tumor. Currently-available therapy carries a significant risk of major side effects, including incontinence and impotence, and consequently many men are reluctant to accept treatment at an early stage of the disease. The need to improve the treatment of prostate cancer is underlined by the existence of over 150 clinical trials world wide (Future Oncology, vol. 4, number 3, 1998).
The expression of the vasopressin gene is largely restricted to hypothalamic neurons, and it encodes for a protein product of ˜17 kDa, to which an N-glycosidic side-chain of ˜4 kDa is added, resulting in the ˜20 kDa provasopressin (pro-VP) precursor. This protein is normally packaged into secretory vesicles where it undergoes enzymatic cleavage to generate vasopressin (VP), VP-associated neurophysin (VP-NP), and VP-associated glycopeptide (VAG) (North, W. G. In: D. Gash and G. Boer (eds.), Vasopressin: Principles and Properties, pp. 175-209, New York: Plenum Press, 1987). These components are then secreted into the circulation. SCLC tumors and cultured cells also express the VP gene, however intact provasopressin protein can become localized to the cell surface plasma membrane (Friedmann et al., B. J. Cancer 69: 260-263, 1994; North et al., Ann. NY Acad. Sci. 689: 107-121, 1993). Polyclonal antibodies raised against VP-NP bind specifically to the surface of cultured SCLC cells, as determined by immunofluorescent analysis (Friedmann et al., Neuropeptides 28: 183-189, 1995; North et al., Prog. Brain Res. 60: 217-225, 1983; North and Yu, Regulatory Peptides 45: 209-216, 1993). Thus, the target of these antibodies has been termed neurophysin-related cell surface antigen (NRSA) (North et al., Peptides 14: 303-307, 1993). Polyclonal anti-VP-NP antibodies recognize proteins of ˜20 kDa and ˜40 kDa in total protein extracts from SCLC cultured cells by Western analysis (North et al., Peptides 14: 303-307, 1993). The ˜20 kDa protein corresponds in size to the provasopressin protein, and the ˜40 kDa protein is believed to be a related form (Camier et al., FEBS Lett., 108: 369-373, 1979; Lauber et al., FEBS Lett., 97: 343-347, 1979; Lauber et al., Proc. Natl. Acad. Sci. USA, 78: 6086-6090, 1981; Moore and Rosenior, Prog. Brain Res. 60: 253-256, 1983; Nicolas et al., Proc. Natl. Acad. Sci. USA, 77: 2587-2591, 1980; Rosenior et al., Endocrinology, 109: 1067-1072, 1981). Polyclonal antibodies that have been raised against the vasopressin, VP-NP, or VAG regions of the pro-VP protein display specific staining of SCLC tumor sections, whereas they exhibit a very low incidence of immunoreactivity with the non-neuroendocrine lung tumors examined (Friedmann et al., B. J. Cancer 69: 260-263, 1994; Friedmann et al., Cancer Letters 75: 79-85, 1993).
Breast cancer is a leading cause of death among women throughout the world, and accounts for the death of approximately 50,000 women in the United States each year (American Cancer Society, Cancer Facts and Figures, Atlanta, Ga.: American Cancer Society, 1993). Although there have been many recent advances for effectively treating this disease (Silverstein, M. J. et al., The Breast Journal (2002) 8:70-76), successful intervention still heavily relies on early detection through mammography and surgical removal of cancerous tissue. As for small cell lung cancer (SCLC), products of the vasopressin (VP) gene appear to present a universal tumor marker system for breast cancer/ductal carcinoma in situ (DCIS) that could provide advanced warnings of early post-oncogenic tissue changes, precise methods for identifying and evaluating changes in tumor burden, and new non-surgical methods of treatment that are effective in providing long-term survival for patients (North et al. Br. Can. Res. Treat. (1995) 34: 229-235; and North Exper. Physiol. (2000) 85S: 27-40). Alternatively, no evidence has been found for expression by normal breast tissues or by various fibrocystic conditions, including atypical hyperdisplasia (North et al., Endocrin. Pathology, In Press, June, 2003). Expression of the VP gene in breast cancer gives rise to surface markers named GRSA (North Exper. Physiol. (2000) 85S: 27-40). These markers interact with polyclonal antibodies recognizing provasopressin and seem to have molecular weights of 40 and 20 kilodaltons. Since the antibodies were first found to interact with glycopeptide moiety of provasopressin, the antigen has been called GRSA (i.e., Glycopeptide-Related cell Surface Antigen).